The objective is to achieve combination chemotherapy of cancer with the aid of metabolic modulation of relevant enzymatic pathways by appropriate metabolite-antimetabolite combinations selected on the basis of both existing biochemical knowledge and that generated from the proposed biochemical studies. Normal and comparatively innocuous compounds are employed either to selectively enhance the antitumor potency of known agents (e.g., thymidine with 5-Fluorouracil), or to protect normal tissue from toxicity (e.g., testosterone and/or uridine with 5-FU). The methodology is step-wise. First, agents selected on the basis of a biochemical rationale are combined in vivo for potential gain in anti-cancer activity. If this is accompanied by untoward toxicity, the next step is the addition of an agent or normal metabolite to selectively protect the host. This procedure continues with the addition of another drug to yield further augmentation of tumor toxicity, and so on. This different approach seeks the control of serious host toxicity as essential to the achievement of chemotherapeutic cure, because the resulting operational increase in drug selectivity will allow both a quantitative and a qualitative increase in the chemotherapeutic drug combination. The validity of this approach is substantiated by previous work. Three individual research projects (Experimental Chemotherapy, Biochemistry, and Clinical Studies) are integrated to accomplish the program objective, supported by an Animal Colony (Core Component). Experimental Chemotherapeutic results from a particular drug manipulation (in clinically relevant murine tumor models), obtained as expected on the basis of a biochemical rationale, will be confirmed on a biochemical level to insure that the results are related to the predicted biochemical changes. Unexpected results require biochemical exploration which will often provide information that can be utilized to alter the drug combination so as to achieve the desired therapeutic advance. Ultimately, the experimental therapeutic findings (substantiated at the biochemical level) sets the course for the Clinical Studies. Similarly, feed-back from the Clinical Studies suggests new experimental studies and directions.